This final revision of an R03 application will examine the effects of marijuana on visuospatial memory on hippocampal function using functional magnetic resonance imaging (fMRI). A number of animal studies have demonstrated hippocampal abnormalities after exposure to cannabinoids, suggesting that key deficits in cognitive processing associated with cannabis use may be related to hippocampal function. It has been shown that cannabis affects memory, frontal and executive function, decision-making and motor skills. However, previous studies have not systematically assessed hippocampal spatial processing. Due to the high concentrations of cannabinoids in the human hippocampus, the effects of cannabis in this brain region are of significant interest. Furthermore, most studies have enrolled predominantly male subjects making it difficult to examine the interactive effects between gender and cannabis use. The specific aims of the current proposal are 1a) to evaluate the effects of marijuana on fMRI BOLD signal changes during hippocampus-mediated challenge paradigms assessing both spatial memory and associative visual memory tasks; 1b) to evaluate the effects of marijuana on performance of visuospatial tasks and the relationship with fMRI BOLD activity; 2) and to examine sex differences in these responses for both marijuana using and non-using subjects. The proposed study will compare 10 male and 10 female current heavy marijuana smokers and 10 male and 10 female healthy non-smoking controls. Our primary hypothesis is that significant decreases in BOLD response will be found for current marijuana smokers compared with non-smoking controls during completion of hippocampal-dependent memory challenge tasks. Further, we hypothesize differential pattern of neural activation between men and women (regardless of smoking condition) during the cognitive challenge paradigms, as well as a sex differences in their performance of these tasks. Lastly, we predict an interaction between smoking condition and sex, whereby female marijuana smokers will exhibit reduced hippocampal BOLD response and reduced visuospatial performance compared to male controls, male marijuana smokers, and female controls. This investigation is novel in that it includes fMRI challenge paradigms and neuropsychological measures sensitive to hippocampal processing to evaluate temporal lobe changes associated with cannabis use. Given the paucity of data on visuospatial memory function in marijuana users and the interaction with gender, we believe these studies will further our understanding of the neural changes underlying cannabis use and provide new insight into understanding gender effects in substance abusing populations. Current research investigations focusing on the effects of smoking marijuana have reported alterations in brain function and in the ability to complete daily activities, however, few thus far have examined the potential impact on visuospatial memory. The proposed project is designed to examine the effects of marijuana on spatial memory and hippocampal function using customized challenge paradigms in conjunction with functional magnetic resonance imaging (fMRI) techniques. Data from this study will clarify the impact of marijuana use on learning and memory, and may provide new insights for the development of intervention and treatment. [unreadable] [unreadable] [unreadable]